Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes

The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The...

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Autores: Marín-Valls, Roser, Hernández Sánchez, Karel, Bolte, Michael, Parella, Teodor, Joglar Tamargo, Jesús, Bujons, Jordi, Clapés Saborit, Pere
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2020
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/222563
Acesso em linha:http://hdl.handle.net/10261/222563
Access Level:acceso abierto
Palavra-chave:Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
Biocatalytic construction
Quaternary carbons
Aldehydes
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spelling Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to AldehydesMarín-Valls, RoserHernández Sánchez, KarelBolte, MichaelParella, TeodorJoglar Tamargo, JesúsBujons, JordiClapés Saborit, PereAldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to AldehydesBiocatalytic constructionQuaternary carbonsAldehydesThe congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.This project has received funding from the Ministerio de Ciencia e Innovación (MICIN), the Fondo Europeo de Desarrollo Regional (FEDER) (grant RTI2018-094637-B-I00 to P.C. and PGC2018-095808-B-I00 to T.P.), and Programación Conjunta Internacional (PCI2018-092937), through the initiative ERA CoBioTech (Tralaminol). The authors gratefully acknowledge the “Consorci de Serveis Universitaris de Catalunya” (CSUC) for allowing the use of its software and hardware resources.Peer reviewedAmerican Chemical SocietyMinisterio de Ciencia e Innovación (España)Bujons Vilàs, Jordi [0000-0003-2944-2905]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/222563reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094637-B-I00 to P.C.https://doi.org/10.1021/jacs.0c09994Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2225632026-05-22T06:33:51Z
dc.title.none.fl_str_mv Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
title Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
spellingShingle Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
Marín-Valls, Roser
Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
Biocatalytic construction
Quaternary carbons
Aldehydes
title_short Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
title_full Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
title_fullStr Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
title_full_unstemmed Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
title_sort Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
dc.creator.none.fl_str_mv Marín-Valls, Roser
Hernández Sánchez, Karel
Bolte, Michael
Parella, Teodor
Joglar Tamargo, Jesús
Bujons, Jordi
Clapés Saborit, Pere
author Marín-Valls, Roser
author_facet Marín-Valls, Roser
Hernández Sánchez, Karel
Bolte, Michael
Parella, Teodor
Joglar Tamargo, Jesús
Bujons, Jordi
Clapés Saborit, Pere
author_role author
author2 Hernández Sánchez, Karel
Bolte, Michael
Parella, Teodor
Joglar Tamargo, Jesús
Bujons, Jordi
Clapés Saborit, Pere
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Bujons Vilàs, Jordi [0000-0003-2944-2905]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
Biocatalytic construction
Quaternary carbons
Aldehydes
topic Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
Biocatalytic construction
Quaternary carbons
Aldehydes
description The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/222563
url http://hdl.handle.net/10261/222563
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094637-B-I00 to P.C.
https://doi.org/10.1021/jacs.0c09994
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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